A gene is considered a candidate gene for type 2 diabetes in Pimas if 1) it is associated with a diabetic phenotype in another population or 2) it has a physiologically relevant function and is positioned in a chromosomal region that is linked to diabetes. Candidate genes which have been analyzed to date include those genes which are associated with Mody in other populations. We identified several polymorphisms in the HNFl?, HNFlb, and HNF3b genes, but none were associated with early onset diabetes in Pimas. One polymorphism in HNFlb, however, predicts a non-conservative amino acid substitution within a critical region of the protein and therefore is being further investigated for functional variability in transfected cell lines. We have also analyzed candidate genes in an area on chromosome 1 linked to diabetes. No polymorphisms associated with diabetes were identified in the pyruvate kinase or the retinoid X receptor gamma genes. We identified one polymorphism in the promoter and 4 polymorphisms in the 3? untranslated region of the ApoA2 gene which were modestly associated with diabetes. However analysis of ApoA2 serum levels by turbidimetric assays in individuals with these variants did not suggest the polymorphisms result in variability in expression levels of ApoA2. Therefore, our data does not suggest that ApoA2 itself is the gene responsible for the linkage observed on chromosome 1.